1. Technical Field
This invention relates to the coenzyme lipoic acid and more particularly to a method of stabilizing lipoic acid with nicotinamide.
2. Description of Related Art
One of the strongest naturally occurring antioxidants is lipoic acid (LA). α-Lipoic acid is also known as thioctic acid, 1,2-dithiolane-3-pentanoic acid, 1,2-dithiolane-3-valeric acid and 6,8-thioctic acid. α-LA has a chiral carbon atom and occurs in two enantiomeric forms (R- and S-). The form of LA sold in stores is α-lipoic acid, a synthetic mixture of the natural isomer (R-) and the unnatural isomer (S-). The natural form of R-LA is not as stable as the synthetic mixture. One manufacturer, Asta Medica, sells R-LA for diabetes and has made a stable form of R-LA by crystallizing it with Tris buffer, a commonly used synthetic, but unnatural, buffer.
Biologically, LA exists as lipoamide in at least five proteins where it is covalently linked to a lysyl residue. Four of these proteins are α-ketoacid dehydrogenase complexes, the pyruvate dehydrogenase complex, the branched chain keto-acid dehydrogenase complex and the α-ketoglutarate dehydrogenase complex. Three lipoamide-containing proteins are present in the E2 enzyme dihydrolipoyl acyltransferase, which is different in each of the complexes and specific for the substrate of the complex. One lipoyl residue is found in protein X, which is the same in each complex. The fifth lipoamide residue is present in the glycine cleavage system.
Recently LA has been detected in the form of lipoyllysine in various natural sources. In the plant material studied, lipoyllysine content was highest in spinach (3.15 μg/g dry weight; 92.51 μg/mg protein). When expressed as weight per dry weight of lyophilized vegetables, the abundance of naturally existing lipoate in spinach was over three- and five-fold higher than that in broccoli and tomatoes, respectively. Lower concentrations of lipoyllysine were also detected in garden pea, Brussels sprouts and rice bran. Lipoyllysine concentration was below detection limits in acetone powders of banana, orange peel, soybean and horseradish, however.
In animal tissues, the abundance of lipoyllysine in bovine acetone powders can be represented in the following order: kidney>heart>liver>spleen>brain>pancreas>lung. The concentrations of lipoyllysine in bovine kidney and heart were 2.64±1.23 and 1.51±0.75 μg/g dry weight, respectively.
LA in its reduced form as dihydrolipoate (DHLA) possesses two —SH groups which provide a very low oxidation potential to the molecule (−0.29 V). Thus, LA and the DHLA redox together are excellent antioxidants capable of interacting with most forms of reactive oxygen species, recycling other antioxidants and additionally reducing oxidized disulfide groups in biological systems. These molecules then may recuperate their biological reducing power and function. These qualities of LA and DHLA make it also one of the most important molecules in redox signaling. A good example of this is the ability of this metabolically active pair to increase glucose uptake in an insulin-mimic effect.
Various enantiomeric forms of α-LA, and combinations and derivatives thereof (including its reduced form), have been used to treat numerous conditions. For example, U.S. Pat. Nos. 5,650,429 and 5,532,269 disclose the use of LAs in the treatment of circulatory disorders. U.S. Pat. No. 5,569,670 discloses combinations of LAs and vitamins in compositions useful for producing analgesic, anti-inflammatory, antinecrotic, anti-diabetic and other therapeutic effects. U.S. Pat. No. 5,334,612 describes certain alkylated derivatives of LA and their use in treatment of retroviral diseases. U.S. Pat. No. 5,084,481 discloses the use of reduced LA (DHLA) and salts thereof in treating inflammatory diseases. U.S. Pat. No. 6,693,664 discloses use of LA and DHLA in the treatment of diabetes. U.S. Pat. No. 5,508,275 discloses a variety of lipid-selective antioxidants, including lipoic acid derivatives.
LA suffers from certain disadvantages, however. In particular, the natural form R-LA is unstable above 40° C., so it can degrade under some warehousing conditions. Also LA is hygroscopic. What is needed is stabilization of this natural form of LA with a natural salt.